Researchers
and patients advocates are cautiously optimistic that a new focus on proteins
known as amyloids may yet solve the ongoing puzzle of Alzheimer’s disease.

Scientists,
executives, and advocates met by the thousands here in Washington this week for
the Alzheimer’s Association International Conference 2015, and researchers here
unveiled three promising clinical trials aimed at the build up of amyloids in
the brains of sufferers.

Alzheimer’s
disease, which makes up 60-80 percent of dementia cases, is a triple threat: it
has a huge prevalence, enormous healthcare costs, and no preventive measures
and cures. Six drugs have been approved by the Food and Drug
Administration (FDA) that temporarily improve Alzheimer’s symptoms, but none so far
have proven to slow or stop the nerve damage that causes the disease, and death.

The
FDA approved the sixth drug in December 2014. Before that, the last approval of
an Alzheimer’s drug was in 2003—the only drug of 244 tested in clinical trials
from 2002-2012.

Difficulties
of developing effective treatments for Alzheimer’s include the long time to
disease progression, and what scientists call the blood-brain barrier, which
makes it difficult for drugs to access the brain.

Compounding
the problem are the monetary and time costs of drug development. It costs $4
billion-$11 billion to develop one drug and takes an average of 12 years for it
to travel from bench to bedside, according to the InnoThink Center For Research
In Biomedical Innovation. Only 5 in 5,000 drugs that enter preclinical or
animal testing progress to human testing—of those 5 drugs, only one is
approved, according to the FDA.

Yet
hope springs eternal. A bevvy of recent studies have shown that the build up of
beta amyloid and tau proteins—Alzheimer’s grim calling cards—begin attacking
patients’ brains up to 20 years before the disease reveals itself. That has
some scientists hopeful that they can intervene early, before Alzheimer’s
symptoms show.

The
Phase III solanezumab study used and published a “delayed-start” approach:
Patients are randomly assigned to start active treatment at the beginning of
the study or are placed in a group that received placebo for a period of before
being given the active experimental therapy. If the experimental treatment merely
reduces Alzheimer’s symptoms, both the early-start and the delayed-start
participants should experience the same benefit. However, if the treatment actually
slows disease progression, both groups would benefit, but the late starters
would not “catch up” to the early starters, researchers say.

“The
delayed-start patients did not catch up, which is encouraging to us. It
suggests that the treatment effect seen is consistent with a disease-modifying
effect. It also suggests that solanezumab should be started earlier rather than
later,” study author and research advisor at Lilly Hong Liu-Seifert, Ph.D., tells
Provider. “This analysis method is also planned for the ongoing …. study.”

Gantenerumab’s
experienced a revival of becoming a viable drug as a result of a Phase III study
that showed reductions of amyloid and tau levels. In December 2014, a 2-year,
Phase trial of people with early symptoms of Alzheimer’s was halted due to
preliminary results indicating that those treated with the drug did not
experience any cognitive benefit compared to patients on placebo.

The new drug on the block, aducanumab, showed great promise
in March, when Biogen showed that after one year, a dose-response effect was
seen:In a pre-specified
analysis across placebo and all doses of aducanumab, treatment of prodromal and
mild Alzheimer’s disease patients with aducanumab resulted in a statistically
significant, dose-dependent reduction in amyloid plaque, as well as a dose-dependent
slowing of cognitive decline. But one hitch was seen:
the 10 milligram dose, while being the most effective, also carried the serious
side effect of ARIA (amyloid-related imaging abnormalities) that results in
dangerous brain swelling. Biogen revealed today the results of its Phase IB
study that included a fourth dose, 6 milligrams, which it hoped to fall into
the dose-dependent response previously seen: highly effective yet without too
many side effects. This dosage fell between that of 3 and 10 milligrams—ARIA
was seen but at a lowered and more tolerated level.

“It
all comes down to that one dose may not fit all subjects. One may need to find
a trial dose that fits best for each patient,” principal Biogen investigator Jeff Sevigny, M.D., tells Provider. His
research team are now moving to a Phase III trial in which a low- and a
high-dose will be given to APOE4 gene carriers (those who have a high risk of
developing ARIA) and APOE4-non-carriers.

Once
stagnant, the field is now experiencing tremendous growth and promise.

Maria
Carrillo, Ph.D., chief scientific officer of the Alzheimer’s Association, echoes this
sentiment: “The data from these new analyses present exciting possibilities,
and we look forward to the results of future studies in these experimental
drugs.”

Jackie Oberst is
Provider’s Managing Editor. Email her at joberst@providermagazine.com. Follow
the magazine on Twitter @ProviderMag.